Neurogenesis is a vital process in the brains of animals and humans, whereby new nerve cells are continuously generated throughout the life span of the organism. The newly born cells are able to differentiate into functional cells of the central nervous system and integrate into existing neural circuits in the brain. Neurogenesis is known to persist throughout adulthood in two regions of the mammalian brain: the subventricular zone (SVZ) of the lateral ventricles and the dentate gyrus of the hippocampus. In these regions, multipotent neural progenitor cells (NPCs) continue to divide and give rise to new functional neurons and glial cells (for review Gage Mol Psychiatry. 2000 May; 5(3):262-9). It has been shown that a variety of factors can stimulate adult hippocampal neurogenesis, e.g., adrenalectomy, voluntary exercise, enriched environment, hippocampus dependent learning and anti-depressants (Yehuda. J Neurochem. 1989 July; 53(1):241-8, van Praag. Proc Natl Acad Sci USA. 1999 Nov. 9; 96(23):13427-31, Brown. J Eur J Neurosci. 2003 May; 17(10):2042-6, Gould. Science. 1999 Oct. 15; 286(5439):548-52, Malberg. J Neurosci. 2000 Dec. 15; 20(24):9104-10, Santarelli. Science. 2003 Aug. 8; 301(5634):805-9). Other factors, such as adrenal hormones, stress, age and drugs of abuse negatively influence neurogenesis (Cameron. Neuroscience. 1994 July; 61(2):203-9, McEwen. Neuropsychopharmacology. 1999 October; 21(4):474-84, Kuhn. J Neurosci. 1996 Mar. 15; 16(6):2027-33, Eisch. Am J Psychiatry. 2004 March; 161(3):426).
Serotonin (5-hydroxytryptamine, 5-HT or 5HT) has been proposed to assert its effects through a number of membrane-bound receptors. The 5-HT or 5HT family of receptors include multiple subtypes. The 5HT1a (or serotonin) receptor subtype is one member of the 5HT1 receptor family. Many members of the family, including 5HT1a, belong to the G protein-coupled receptor (GPCR) superfamily. According to some studies, 5HT1a receptor agonists are thought to inhibit activation of adenylate cyclase in some cells, leading to decreases in cAMP. Another study suggests that the 5HT1a receptor is coupled to N- and L-type calcium channels in some ganglion cells (see Cardenas et al. J. Neurophysiol. 77(6):3284-96, 1997).
5HT1a receptors are distributed in the CNS, and their activation has been shown to lead to neuronal hyperpolarization. The role of 5HT1a receptors has been thought to relate to modulation of anxiety, in part because knockout mice lacking 5HT1a receptors display increased anxiety. The animals also display reduced immobility in forced swimming and tail suspension tests. Agonists of 5HT1a, such as buspirone or gepirone, have been used as anxiolytics (see Tunnicliff Pharmacol. Toxicol. 69:149, 1991; and Den Boer et al. Hum Phychopharmacol. 15:315, 2000). Another 5HT1a agonist is 8-hydroxy-2-(di-n-propylamino), where the R(+)-isomer is a full agonist and the S(−)-enantiomer is a partial agonist.
Antagonists of 5HT1a may be used to accelerate the effects of selective serotonin reuptake inhibitors (SSRIs) and enhance their clinical efficacy (see Arborelius et al. Naunyn-Schmeiedebergs Arch Pharmacol 353:630-640, 1996). Examples of 5HT1a antagonists include spiperone and pindolol.
The 5HT4 receptor is another subtype, with multiple C-terminal splice variants having been described as 5HT4A through 5HT4H (see Blondel et al. (1997) FEBS Lett. 412:465; Blondel et al. (1998) J. Neurochem 70:2252; Claeysen et al. (1997) Neuroreport 8:3189; Claeysen et al. (1999) Mol. Pharmacol. 55:910; Van Den Wyngaert et al. (1997) J. Neurochem. 69:1810; Mialet et al. (2000) Br. J. Pharmacol. 129:771; and Mialet et al. (2000) Br. J. Pharmacol. 131:827. Most members of the family, including 5HT4, belong to the G protein-coupled receptor (GPCR) superfamily. According to some studies, 5HT4 receptor agonists have been observed as leading to increases in cAMP. The splice variants have been reported to couple positively to adenylyl cyclase and have been observed to have similar pharmacological properties.
5HT4 receptors have been reported as displaying constitutive, agonist-independent, activity. The activity has been observed at relatively low receptor levels which may explain detected silent or inverse agonist activity by some putative antagonists.
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